Towards Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor
Abstract
Both dopamine D-3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 26, 2017
- Accession Number
- AD1119293
Entities
People
- Alessandro Bonifazi
- Amy H. Newman
- Clare Zhu
- Comfort A. Boateng
- Hideaki Yano
- Jeffrey R. Descamps
- Jonathan Javitch
- Lei Shi
- Mayako Michino
- Michael P. Ellenberger
- Oluyomi M. Bakare
- Prashant Donthamsetti
- Ravi Verma
- Thomas M. Keck
- Vivek Kumar
Organizations
- National Institutes of Health
- New York State Psychiatric Institute
- Rowan University
- United States Naval Research Laboratory